tbuckley/cabot-search huggingface dataset:
Abstract 262: Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling
Authors: Chiho Nakashima, Yukimasa Shiotsu, Yohei Harada, Hiroo Katsuya, Emi Ookuma, Masanori Nishi, Akemi Sato, Hideaki Nakamura, Naoko Sueoka-Aragane
Journal: Cancer Research (2023)

Abstract Background: Cancer genome profiling using next-generation sequencing (NGS) has become widespread. Multiple genetic abnormalities including variant of unknown significance (VUS) have been detected in various cancer types. However, there is a lack of an integrated analysis system capable of identifying relationships among multiple genetic abnormalities and weighting them appropriately. Here, we report heat map analysis, a new integrated pathway scoring system for cancer genome profiling. Methods: In heat map analysis, approximately 180 cancer-related genes among 324 genes evaluated by FoundationOne CDxTM are scored based on gene annotation and variant allele fraction (VAF), and classified into 16 pathways. This system provides an overall picture of genetic abnormalities and easy recognition of abnormal pathways. To examine the usefulness of the heat map analysis, a retrospective observational study was conducted on 50 patients with solid tumors who underwent cancer genome profiling test at Saga University Hospital from June 2019 to February 2022. The primary end point was the presentation rate of pathways with significantly increased scores. Results: A total of 749 genetic abnormalities including VUS were detected in 50 patients with 15 cancer types: 571 single nucleotide variants (SNVs), 156 copy number variants (CNVs), and 22 fusions. The median number of abnormalities detected was 11 (2-20) SNVs, 2 (0-23) CNVs, and 0 (0-4) fusions, respectively. Heat map analysis presented active pathways with significant score elevation in 42 cases (84%). The TP53 pathway was the most common, followed by the Receptor Tyrosine Kinase pathway, PIK3-AKT, RAS, and DNA repair-related pathways. Conclusion: Heat map analysis could be a promising new method for integrated analysis using cancer genome profiling tests. Citation Format: Chiho Nakashima, Yukimasa Shiotsu, Yohei Harada, Hiroo Katsuya, Emi Ookuma, Masanori Nishi, Akemi Sato, Hideaki Nakamura, Naoko Sueoka-Aragane. Heat Map Analysis, a new integrated pathway scoring system for cancer genome profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 262.
Abstract 227: In vivo functional genomics screen to uncover tumor intrinsic negative regulators of NK cell-mediated tumor cell killing
Authors: Kayla Duval, Elsa Krall, Federica Piccioni, Maria Monberg, Marianne Spatz, Tobias Ehrenberger, Nicole Follmer
Journal: Cancer Research (2023)

Abstract Natural killer cells are innate immune cells whose activity is gated by activating and inhibitory receptors that bind ligands on potential target cells. NK cell gene signatures are associated with improved survival in several indications, and NK cell therapies have shown some encouraging results in the clinic. These data highlight the relevance of this cell type in anti-tumor immunity and has given rise to interest in amplifying NK responses to cancer as a complementary therapeutic strategy to current T cell based immunotherapies. The goal of this project is to identify tumor cell intrinsic negative regulators of NK cell-mediated tumor cell killing through in vivo CRISPR/Cas9 screening, with identification of both PD-1 blockade-dependent and -independent regulators. The syngeneic B16F10 model in C57Bl6 mice was used with or without NK depletion and with or without anti-PD1 treatment, with a custom library of 900 genes split into four subpools (one guide per gene per subpool). B16F10 cells were transduced in vitro and inoculated into mice ten days after spinfection. On day 14 after inoculation, tumors were harvested and subsequently the gDNA was isolated and sequenced. QC analysis indicated good guide recovery and screen performance. There were several hits from this screen that were depleted in the NK+ context but not in the NK depleted context, indicating their potential role in regulating NK mediated cell killing. Of the hits, several expected genes scored including B2M which is a known negative regulator of NK cell killing. Validation efforts include confirmation of dropout in other models as well as in vitro co-culture assays to assess enhanced NK killing of single gene KO cells. The hits identified in the screen will increase our understanding of anti-tumor immunity and serve as potential novel Oncology targets. Citation Format: Kayla Duval, Elsa Krall, Federica Piccioni, Maria Monberg, Marianne Spatz, Tobias Ehrenberger, Nicole Follmer. In vivo functional genomics screen to uncover tumor intrinsic negative regulators of NK cell-mediated tumor cell killing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 227.
Abstract 6011: Methylation profiling reveals the role of PRC2 in regulating DNA methylome changes in malignant peripheral nerve sheath tumors
Authors: Christopher M. Stehn, Minu Bhunia, Kyle B. Williams, Alex T. Larsson, David A. Largaespada
Journal: Cancer Research (2023)

Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer predisposition syndrome defined by germline deletion of one NF1 allele. Somatic loss of heterozygosity in the remaining NF1 allele in Schwann lineage cells gives rise to benign tumors known as plexiform neurofibromas. These tumors have a high risk of developing into cancerous lesions known as malignant peripheral nerve sheath tumors (MPNST) through the sequential deletion of CDKN2A/B followed by recurrent mutations in SUZ12 or EED, constituting the inactivation of polycomb repressor complex 2 (PRC2). PRC2 is a transcriptional repressor complex involved in the silencing of several genes throughout cell development and differentiation. Loss of this complex leads to a depletion in trimethylation marks on Histone H3 Lysine 27 (H3K27me3) and the subsequent gain of acetylation marks on the same lysine residue (H3K27Ac). However, full range of epigenetic consequences of these events are currently not well characterized, especially with respect to MPNST formation and development. The Largaespada lab has developed Schwann cell lines engineered to harbor deletions in NF1 and either SUZ12 or EED and assayed the methylation status of 850,000 CpG sites using the EPIC array. The resulting methylation profiles reveal a large degree of change in promoter methylation between cell lines with and without PRC2 inactivation. These changes, however, appear to be inconsistent. To further understand this phenomenon, I have analyzed differential methylation patterns between lines with SUZ12/EED deletions on top of NF1 deletion compared to those with NF1 deletion alone. Pathway analysis of genes whose promoters are differentially methylated upon PRC2 reveals a bias towards developmental modules such as morphogenesis and neuronal differentiation, suggesting that DNA methylation is a mechanism by which PRC2 loss promotes stemness in Schwann lineage cells prior to MPNST formation. Additionally, differentially methylated regions were overlapped with functional non-coding elements in the genome to understand potential ripple effects in the epigenome. These findings underline the importance of DNA methylation in contributing to tumor formation and define unique functions by which PRC2 specifically leverages diverse methylation states to drive malignant transformation in Schwann lineage cells. Citation Format: Christopher M. Stehn, Minu Bhunia, Kyle B. Williams, Alex T. Larsson, David A. Largaespada. Methylation profiling reveals the role of PRC2 in regulating DNA methylome changes in malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6011.
NCCN Guidelines® Insights: Non–Small Cell Lung Cancer, Version 2.2023
Authors: David S. Ettinger, Douglas E. Wood, Dara L. Aisner, Wallace Akerley, Jessica R. Bauman, Ankit Bharat, Debora S. Bruno, Joe Y. Chang, Lucian R. Chirieac, Malcolm DeCamp, Thomas J. Dilling, Jonathan Dowell, Gregory A. Durm, Scott Gettinger, Travis E. Grotz, Matthew A. Gubens, Aparna Hegde, Rudy P. Lackner, Michael Lanuti, Jules Lin, Billy W. Loo, Christine M. Lovly, Fabien Maldonado, Erminia Massarelli, Daniel Morgensztern, Thomas Ng, Gregory A. Otterson, Sandip P. Patel, Tejas Patil, Patricio M. Polanco, Gregory J. Riely, Jonathan Riess, Steven E. Schild, Theresa A. Shapiro, Aditi P. Singh, James Stevenson, Alda Tam, Tawee Tanvetyanon, Jane Yanagawa, Stephen C. Yang, Edwin Yau, Kristina M. Gregory, Miranda Hughes
Journal: Journal of the National Comprehensive Cancer Network (2023)

The NCCN Guidelines for Non–Small Cell Lung Cancer (NSCLC) provide recommendations for management of disease in patients with NSCLC. These NCCN Guidelines Insights focus on neoadjuvant and adjuvant (also known as perioperative) systemic therapy options for eligible patients with resectable NSCLC.
Abstract 2591: Role of Rab25 in Melanoma and its potential targeting
Authors: Samikshya Kandel, Krishna Rao
Journal: Cancer Research (2023)

Abstract Background: RAB25 is a protein that belongs to the RAB11 subfamily located in the lq22 locus of chromosome and is ubiquitously expressed in cells of the gastrointestinal mucosa, ileum, and kidney. Its role in tumorigenesis is variable but is unclear in the case of melanoma progression. Our previous studies showed that loss of RAB25 has a special role in mediating the tumorigenic transformation of human mammary epithelial cells. Its loss particularly cooperated with mutant Ras isoforms to promote transformation in vitro. We are now examining the role of RAB25 in melanomas as melanomas exhibit a high rate of N-Ras mutations. We hypothesize that the presence of NRAS types of mutation and expression of RAB25 are mutually exclusive as RAB25 functions are a tumor suppressor to inhibit this mutation. Methods: Different NRAS mutant melanoma cell lines (SKMEL-2, SKMEL-28, WM1366 and WM266-4) were examined forRab25 expression through qRT-PCR and Western Blotting. The positive control was MCF cell lines and MDA-MB-231 was considered as negative control. Immunohistochemistry was done with biopsy proven melanoma tissue samples and normal adjacent tissue to observe the trend of Rab25 expression. Keratinocytes and fibroblasts in the tissue samples were considered as internal controls.Results: We found a significant decrease in Rab25 expression in NRAS mutant melanoma cell lines compared to Raf mutants and primary melanocytes. The reduction was prominent at both the RNA and protein level. RAB25 expression was also reduced in melanoma tumors as compared to surrounding tissue. Conclusion: RAB25 loss may indeed cooperate with NRAS mutation to promote transformation in melanomas. Further studies including overexpression experiment in the cell line model followed by migration assay, invasion assay, and in vivo nude mouse experiments will provide further confirmation of our hypothesis. Citation Format: Samikshya Kandel, Krishna Rao. Role of Rab25 in Melanoma and its potential targeting [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2591.
Abstract 1769: A combination approach of a cellular library and single cell microfluidics analysis for the rapid selection of CAR-T cells
Authors: Eren Boga, Luisa Berger, Alice De Roia, Inka Zörnig, Robert Embacher, Stefan B. Eichmüller, Dirk Jäger, Richard Harbottle, Patrick Schmidt
Journal: Cancer Research (2023)

Abstract Within the last decade CAR-T cells have changed the landscape of treatment regimen for leukemia and myeloma, which is reflected by the first FDA approval of this class of living drugs in 2017. As of today, the clinical trial situation aims on CAR-T applicability in solid tumors, which is more arduous due to antigen heterogeneity and limited CAR-T persistence. More personalized and multi-target oriented cellular products may offer a solution to overcome these problems but then CAR identification and selection display the major bottleneck in the drug development process. Usually, matching scFvs are selected from targeting screens of a phage-display library and hits are subsequently cloned in CAR backbones and tested for functionality and possible limiting factors as the occurrence of tonic signaling. This makes the whole process very time consuming and laborious. Within this project, we propose a novel CAR-T selection method that rapidly shortens the discovery procedure. We have developed a full length CAR library in nS/MARt DNA vectors that is electroporated in a Jurkat reporter cell line reflecting entirely its full diversity. By this, we can quickly identify the amount of tonic signaling CARs and exclude them from further selection. For on-target selection we first perform a bulk pre-selection followed by a single cell functionality screening using the Berkeley Lights Lightning™ device. This allows us to export hits as clonal viable cells that undergo long length Nanopore CAR-RNA sequencing. Our findings show the feasibility of our approach and that it can shorten the timeframe needed for the full selection process from weeks to days. Citation Format: Eren Boga, Luisa Berger, Alice De Roia, Inka Zörnig, Robert Embacher, Stefan B. Eichmüller, Dirk Jäger, Richard Harbottle, Patrick Schmidt. A combination approach of a cellular library and single cell microfluidics analysis for the rapid selection of CAR-T cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1769.
Abstract 1948: Novel insights into lung cancer &amp; chronic obstructive pulmonary disease racial disparities
Authors: Jose Thomas Thaiparambil, Zheng Yin, Randa El-Zein
Journal: Cancer Research (2023)

Abstract Introduction: Lung cancer (LC) and chronic obstructive pulmonary disease (COPD) result from the dual effects of smoking/pollution exposure and genetic susceptibility. Blacks/African Americans (B/AA) have higher tobacco-related morbidity and mortality than Whites/European Americans (W/EA), despite smoking fewer cigarettes and starting later in life. COPD is a well-established risk factor for LC and B/AA develop COPD with less cumulative smoking and at younger ages. We will test the hypothesis that NRF2 and Focal Adhesion-PI3K-Akt-mTOR-signaling pathways play a significant role in the disparities observed between B/AA and W/EA with LC and COPD and that account for worsened outcomes in B/AA. Methods: RNAseq analysis was conducted on tissues from 30 LC patients and 29 COPD patients undergoing lung transplantation. We compared both LC and COPD RNAseq data to identify common and unique transcripts associated with each disease. Results: A total of 153 genes were significantly upregulated in COPD compared to LC adeno carcinoma and 174 LC squamous cell carcinoma. Ingenuity pathway analysis revealed the involvement of top regulator networks with the activation of EPSA1, CTNNB1, EP300, IKBKB and IL1B which are seen in both LC and COPD and may be involved in COPD progression to LC. We further analyzed the transcriptome of COPD between B/AA and W/EA and identified 141 significantly upregulated genes in B/AAs. We further validated our findings in TCGA B/AA LC patients to determine the extent of overlap between COPD and LC. Among these, 42 (29.8%) and 13 (9.2%) genes were significantly upregulated in TCGA LC adenocarcinoma (58 B/AA patients vs 527 from other races) and LC squamous cell carcinoma cohorts (32 B/AA patients vs 518 from other races), respectively. Survival analysis using the upregulated genes from the TCGA LC B/AA cohorts showed a higher expression of three LC adenocarcinoma (TOMM5, CEP-152 and HGS) and two LC squamous cell carcinoma specific genes (PYROXD2 and USP43) significantly associated with overall survival. Conclusion: Our data provide novel insight on the overlap between COPD and LC and identified potential pathways that may be contributing to the significant health care disparity among B/AAs. Future studies are warranted to identify early-stage COPD markers that could be used for identification of high-risk individuals that would benefit from therapeutic interventions. Citation Format: Jose Thomas Thaiparambil, Zheng Yin, Randa El-Zein. Novel insights into lung cancer &amp; chronic obstructive pulmonary disease racial disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1948.
Abstract 2838: Tumor-targeted interleukin-2 enhances the anti-cancer activity of multivalent OncoFAP radioligand therapeutics
Authors: Andrea Galbiati, Matilde Bocci, Ettore Gilardoni, Aureliano Zana, Dario Neri, Samuele Cazzamalli
Journal: Cancer Research (2023)

Abstract Radioligand Therapeutics (RLTs) are products composed of a tumor-targeting small organic ligand and a biocidal radioactive payload. The therapeutic potential of RLTs strongly depends on their uptake and residence time in tumors and in the healthy structures after administration. Fibroblast Activation Protein (FAP) is a cell surface antigen abundantly expressed in the microenvironment of the majority of solid human cancers of epithelial origin. We have recently described OncoFAP, an ultra-high affinity ligand of FAP whose targeting performances have been validated by Nuclear Medicine in patients with a wide variety of solid malignancies. Multivalent OncoFAP radioligand therapeutics (OncoFAP-RLTs) show high and prolonged tumor uptake with favorable tumor-to-organ ratios. Here we describe the development of novel multivalent OncoFAP-RLTs and their combination with a clinical-stage tumor-targeted interleukin-2 (L19-IL2). We designed and synthesized a set of multivalent OncoFAP derivatives, aiming at maximizing their affinity for the target protein and their residence time in the catalytic pocket of FAP. The multivalent ligands were coupled to the DOTAGA chelator, suitable for radiolabeling with 177Lu for therapeutic application. The tumor targeting properties of the multivalent OncoFAP ligands were investigated in a comparative biodistribution study in SK-RC-52.hFAP tumor-bearing mice. 177Lu-OncoFAP-23 emerged for its superior uptake and residence time in tumors and for its favorable tumor-to-kidney ratio. Moreover, when administered at very low dose 177Lu-OncoFAP-23 exhibited an enhanced anticancer activity compared to a monovalent (177Lu-OncoFAP-DOTAGA) and bivalent (177Lu-BiOncoFAP-DOTAGA) version of OncoFAP. When OncoFAP-based RLTs were combined with L19-IL2, a strong synergistic anticancer activity was observed. This synergy is driven by NK-cell mediated immune response directed to the tumor, with the concomitant release of granzymes and other pro-apoptotic proteins in the tumor microenvironment. Our findings heighten OncoFAP-based RLTs as promising anti-cancer drugs for treatment of FAP-positive tumors, alone or in combination with targeted interleukin-2. Citation Format: Andrea Galbiati, Matilde Bocci, Ettore Gilardoni, Aureliano Zana, Dario Neri, Samuele Cazzamalli. Tumor-targeted interleukin-2 enhances the anti-cancer activity of multivalent OncoFAP radioligand therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2838.
Abstract 2833: Exploring the impact of IL-17 pathway modification on radiation dermatitis and radiation therapy efficacy
Authors: Megan E. Pirtle, Yana Kost, Alana Deutsch, Kosaku Shinoda, Beth N. McLellan
Journal: Cancer Research (2023)

Abstract Here we explore the role of Interleukin-17 (IL-17) in the promotion of radiation dermatitis (RD) and radiation therapy (RT) efficacy. RD is a common and potentially treatment-limiting skin toxicity that occurs following RT. When the treated tumor is close to the skin, as in head and neck or breast cancer, RD is the most common acute adverse event which negatively impacts patients’ quality of life; however, evidence-based treatments are limited. We performed RNA sequencing of RT-treated skin in both human skin and a murine model, which each showed increased expression of IL-17 Receptor type C (IL-17RC). To further explore the role of the IL-17 pathway in the development of RD, both genetic knockout of IL-17RC and pharmacologic blocking of IL-17A in mouse models were studied, and both were found to have attenuated histopathological signs of RD, including inflammation, acanthosis, and fibrosis when compared to controls. After establishing the importance of the IL-17 pathway on RD, we explored the impact of such IL-17 pathway modification on the anti-tumorigenic efficacy of RT, an important step when considering a future IL-17 neutralizing therapy for RD. A Trans-PyMT murine model of triple-negative breast cancer was used to evaluate the impact of IL-17A neutralization on RT efficacy. There was no difference found in the efficacy of RT in mice treated with IL-17A neutralizing antibody as compared with saline control. Overall, we present a clinically relevant murine model which advances our understanding of the immunopathogenesis of RD and suggests further exploration of targeted therapies for RD prophylaxis is warranted. Additionally, we show that modifying the IL-17 pathway is effective in mitigating RD phenotype with no impact on RT efficacy. Citation Format: Megan E. Pirtle, Yana Kost, Alana Deutsch, Kosaku Shinoda, Beth N. McLellan. Exploring the impact of IL-17 pathway modification on radiation dermatitis and radiation therapy efficacy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2833.